Targeting Metalloenzymes for Therapeutic Intervention

Abstract

Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

Nanocatalytic Medicine

“…Importantly, from the perspective of structure–property relationship, given that single‐atom catalysts (SACs) with M–N–C structure (M refers to Fe, Mn, Co, etc.) possess similar M–N x sites with natural metalloenzymes, it is expected that this type of SACs can serve as single‐atom nanozymes to mimic the catalytic activity of natural enzymes, such as peroxidase, for the efficient catalytic treatment of bacterial infection. Very recently, Liu and co‐workers first demonstrated that MOF‐derived mesoporous carbon nanospheres containing zinc‐centered porphyrin‐like structure (PMCS) could serve as a single‐atom nanozyme with peroxidase‐like activity, which could inhibit up to 99.87% Pseudomonas aeruginosa and resultantly promote wound healing ( Figure ) 32a.…”

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

“…In metalloenzyme inhibition, the carboxylic acid motif routinely participates in metal coordination,a ss een in inhibitors for neutral endopeptidase (NEP), class II fructose-1,6-bisphosphate aldolase (FBP-aldolase), angiotensin-converting enzyme (ACE), and many others. [40] Despite the efficacy of this functional group, its usefulness can be limited in drug development due to poor cell permeability, metabolic instability,a nd off-target effects. [37,39] In an attempt to overcome such liabilities,c hemists turn to the use of prodrugs or isosteric replacement.…”

“…Ap rominente xample includes substituting the carboxylic acid functional group with carboxylic acid isosteres. [40] Despite the efficacy of this functional group, its usefulness can be limited in drug development due to poor cell permeability, metabolic instability,a nd off-target effects. [37][38][39] The ionizable nature of the carboxylic acid under physiological conditions (pH 7.4) makes it au seful handle for generating strong inhibitor-target interactions (i.e., electrostatic and hydrogen bonds).…”

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…The selected targets were: the polymerase acidic Nterminal (PA N ) endonuclease domain from the H1N1 inuenza A virus (antiviral target), New Delhi metallo-b-lactamase-1 (NDM-1; antibacterial target), and the N-terminal domain of heat shock protein 90-a (Hsp90; anticancer target). 47,48 The role of these enzymes in their respective diseases and inhibitor development for each are presented elsewhere. [47][48][49] Briey, PA N endonuclease is one of three proteins in the RNAdependent RNA polymerase complex of the inuenza A virus, along with the polymerase basic protein 1 (PB1) and the polymerase basic protein 2 (PB2).…”

“…47,48 The role of these enzymes in their respective diseases and inhibitor development for each are presented elsewhere. [47][48][49] Briey, PA N endonuclease is one of three proteins in the RNAdependent RNA polymerase complex of the inuenza A virus, along with the polymerase basic protein 1 (PB1) and the polymerase basic protein 2 (PB2). 50 PA N endonuclease contains a dinuclear metal active site, with two Mn 2+ or Mg 2+ cations that promote endonuclease activity.…”